Joseph F. Hayes

Background: Dihydropyridine calcium channel blockers have been implicated in both symptom improvement and exacerbation in pre-existing severe mental illness (SMI). We aimed to test the hypothesis that blood-brain barrier penetrant dihydropyridines (DHPs) reduce rates of mental health hospitalisation and self-harm compared to non-penetrant DHPs. Methods: We used English electronic health records (Clinical Practice Research Datalink) to conduct a target trial emulation study in people with schizophrenia, bipolar disorder or other psychosis. We compared admissions for mental health and self-harm in those prescribed blood-brain barrier penetrant (intervention) and non-penetrant DHPs (control). Our primary endpoint was a 12-month intention-to-treat analysis using covariate adjustment. We additionally completed overlap weighting, per-protocol analyses and negative outcome controls. Results: We included 918 people prescribed blood-brain barrier penetrant DHPs and 3384 prescribed amlodipine (control). In the primary covariate-adjusted intention-to-treat analysis, there was no clear evidence of a difference in rates of combined mental health admissions and self-harm events (adjusted hazard ratio (HR): 1.22; 95% confidence interval (CI): 0.78–1.91 at 12 months). In a pre-specified sensitivity analysis using overlap weighting, self-harm event rates were elevated in the intervention group at 12 months (HR: 2.10; 95% CI: 1.13–3.94); however, the equivalent covariate-adjusted estimate showed no clear difference (HR: 1.81; 95% CI: 0.52–6.26). Conclusion: In people with SMI, blood-brain barrier penetrant DHPs were not associated with reduced mental health hospitalisations or self-harm events compared to those treated with amlodipine, though estimates were imprecise. This active comparator design cannot distinguish between absence of effect or equivalent benefit of both drug classes. There are peripheral pathways through which DHPs may impact psychiatric symptoms and these require further exploration.

Background: Bipolar disorder is an episodic mental illness, often requiring complex pharmacological management. Lithium is a first-line treatment, while antidepressant monotherapy can precipitate mania symptoms in some patients. Aims: To (a) describe patterns of antidepressant, antipsychotic and mood stabiliser prescribing in the 12-month periods before and after first-recorded bipolar diagnosis; (b) describe treatment trajectories in the year post-diagnosis; and (c) investigate associations between sociodemographic and treatment-related characteristics of (i) antidepressant monotherapy and (ii) lithium prescription post-diagnosis. Method: A longitudinal cohort study of patients with a first-recorded diagnosis of bipolar disorder between 2000 and 2022 derived from Clinical Practice Research Datalink. Prescriptions for antidepressants, antipsychotics and mood stabilisers were examined in the 12 months before and after diagnosis. Logistic regression models tested associations between sociodemographic and treatment-related characteristics and prescribing outcomes. A web application ( https://dop-mhds.shinyapps.io/bpd-prescribing-uk-shiny/ ) was developed to visualise treatment trajectories over the year following diagnosis. Results: We included 40 965 patients with a first-recorded diagnosis of bipolar disorder between 2000 and 2022 (median age at diagnosis 43 years, 60.9% female, 11.1% ethnic minority). Of these, 32 460 (79.2%) were prescribed a relevant medication in the year prior to diagnosis compared with 37 208 (90.8%) in the year after. Antidepressant monotherapy was the most common pre-diagnosis treatment (48.4%), but was also prescribed to 28.9% during at least 1 month in the year after diagnosis. Antipsychotic monotherapy was the most common post-diagnosis treatment (36.0%). Lithium was prescribed to 18.5% within 1 year of diagnosis, with 4.0% receiving it as first-line monotherapy. Almost half (46.0%) switched medication at least once within 1 year. Males, ethnic minorities and patients residing in the most deprived areas had lower odds of receiving either lithium or antidepressant monotherapy. Conclusions: Prescribing patterns for bipolar disorder in the UK are highly variable and often outside of guideline recommendations, with persistent use of antidepressant monotherapy and potential under-utilisation of lithium.

Background: Major depressive disorder (MDD) represents a leading cause of global disability, yet prevalence estimates vary dramatically across countries. While individual-level risk factors are well-documented, the role of structural and socioeconomic determinants in explaining cross-national variation remains poorly understood. The present systematic review and meta-analysis aim to estimate pooled global prevalence of MDD, and evaluate the extent to which country-level structural and socioeconomic indicators explain cross-national variation.Methods: MEDLINE, PsycINFO, and EMBASE were searched for articles published in English from 2000 to July 2025. Studies were included if they reported lifetime prevalence and/or 12-month prevalence, defined as the proportion of participants meeting criteria for MDD or MDE at any point in the previous 12 months, according to ICD-10, DSM-IV, or DSM-5 criteria; (2) had at least 1,000 participants; and (3) were published in peer-reviewed journals. Study outcomes included lifetime and 12-month prevalence of MDD or MDE. Random-effects meta-analyses were performed to estimate pooled prevalence. Mixed-effects meta-regressions examined prevalence moderators.Outcomes: Forty-four population-based studies, including 60 independent samples from 44 countries across six continents and a total of 1,149,046 participants were included. Pooled lifetime prevalence was 10.2% (95% CI=8.5 to 11.9%) and 12-month prevalence was 4.9% (95% CI=4.2 to 5.6%). For lifetime prevalence, continent explained 47.8% of variance and income level contributed 10.4%, with upper-middle-income countries showing the lowest prevalence. For 12-month prevalence, employment rate was the only significant moderator (β=-0.07, p=0.04) in univariable analyses, with stronger protective effects in Asia (β=-0.29, p<0.01) and Africa (β=-0.23, p=0.04). Continent and income combined explained 60.7% of between-study lifetime variance, while continent and employment explained 30.7% of 12-month variance. Study-level moderators were mostly non-significant.Interpretation: Structural and socioeconomic determinants partially explain global MDD prevalence, with different factors driving lifetime versus 12-month prevalence, effects varying across continents. Region-specific mental-health strategies should address socioeconomic determinants alongside individual-level interventions.

Schizophrenia is a severe psychiatric disorder with known genetic and socioenvironmental antecedents. We tested whether genetic liability to schizophrenia is associated with socioenvironmental exposures for schizophrenia at birth which could indicate confounding. Data were drawn from the first wave of the 1958 British Birth Cohort, the National Child Development Study (NCDS). We selected 13 socioenvironmental exposures which have been linked to increased schizophrenia risk, including measures of social class, parental demographics, and pre- and perinatal exposures. We applied mutually adjusted regression to test the association between these socioenvironmental exposures and child’s polygenic susceptibility to schizophrenia measured via polygenic index (PGI). The final sample included 6,274 participants. Genetic liability to schizophrenia was not randomly distributed and associated with some socioenvironmental exposures at birth. Children whose mothers smoked more prior to pregnancy had a 0.008 standard deviation (SD) higher schizophrenia PGI per unit increase in cigarettes smoked (95%CI:0.002 to 0.014). Children born to older mothers had lower PGI, with a 0.008SD decrease per additional year of maternal age (95%CI:0.000 to 0.016). Compared with children born in the southeast of England, those born in the north, south, southwest, and Scotland had lower PGI. Children with higher values for the genetic principal component capturing north versus south geographical clustering had higher PGI (0.106 SD per unit; 95%CI:0.076 to 0.136). Children did not differ meaningfully by other socioenvironmental exposures. This has implications for causal inference and Mendelian randomisation studies of schizophrenia, as they may be affected by confounding.

Background: Although lithium has been used effectively as a medication to treat bipolar and major depressive disorders, there are limited data defining lithium use patterns during pregnancy. Aims: To investigate trends and patterns of lithium prescribing in the perinatal period (before, during and after pregnancy) among pregnancies in the UK. Method: We conducted a population-based study using primary healthcare records from the Clinical Practice Research Datalink GOLD, analysing 752 112 pregnancies during the period 1995–2018. We assessed the prevalence and patterns of lithium prescriptions, including discontinuation, continuation and dosage. Maternal characteristics were defined for lithium non-users and users, and between those who continued and discontinued use. Results: From 1995 to 2018, the prevalence of lithium prescribing per 10 000 pregnancies was 3.02 (95% CI: 2.64, 3.44) before pregnancy, 1.89 (95% CI: 1.59, 2.23) during pregnancy and 2.81 (95% CI: 2.44, 3.21) postpartum. Prescribing during pregnancy was low across the study period, with the most recent prevalence in 2018 of 1.03 (95% CI: 0.26, 4.11) per 10 000 pregnancies. Among 337 pregnancies with perinatal lithium prescribing, 48.4% involved a diagnosis of bipolar disorder. Of 227 pregnancies where lithium was prescribed preconception, 15.4% continued treatment throughout pregnancy; discontinuation occurred before pregnancy in 20.7%, and during second or third trimester in 30.8%; 33.0% followed other prescribing patterns. Women who discontinued lithium were more likely to be younger, have a body mass index ≥30 kg/m ² , a diagnosis of bipolar disorder, a history of smoking and >10 primary care consultations in the 12 months preconception, compared with those who continued treatment. Conclusions: Lithium prescribing during pregnancy in the UK is uncommon and discontinuation is frequent, particularly in the later stages of pregnancy. These findings highlight the need for proactive perinatal mental healthcare strategies and close clinical monitoring, to reduce unintentional first-trimester exposure while ensuring continuity of care for maternal mental health.

Background: Consumption of gabapentinoids has increased worldwide in recent years, and the association between its use and drug poisoning is of public health concern. This study aimed to investigate the association between gabapentinoid treatment and the risk of drug poisoning. Methods and findings: In this within-individual study, we utilised data from the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) Aurum database linked to the Hospital Episode Statistics (HES) and Office for National Statistics (ONS). The analysis included individuals aged 18 or above who were prescribed gabapentinoids and had an incident all-cause drug poisoning event between 1st January 2010 and 31st December 2020. Using the self-controlled case series (SCCS) design, we assessed the risk of drug poisoning incidence in predefined risk periods: 90 days before treatment initiation, first 28, 29–56, 57–84 days, and the remaining treatment time. Concomitant use with opioids/benzodiazepines was also evaluated. Adjusted incidence rate ratios (aIRRs) were calculated using conditional Poisson regression. A case-case-time-control (CCTC) analysis was also conducted, with adjusted odds ratio (aOR) calculated to validate the findings from the main SCCS analysis. All analyses have adjusted for key time-varying confounders, including age, season, and concomitant use of opioids, antiseizure medications, psychotropic medications, and non-steroidal anti-inflammatory drugs (NSAIDs). 16,827 individuals met the inclusion criteria and were included in the SCCS analysis. The risk of drug poisoning, compared with the reference periods, increased during the first 28 days of gabapentinoid treatment (aIRR = 1.81, 95% confidence interval [CI] [1.66, 1.99]; p < 0.001), eventually dropped to 1.11 (95% CI [1.05, 1.17]; p < 0.001) in the remainder of the treatment period. Notably, the risk was doubled during the 90-day preceding treatment initiation (aIRR = 2.09, 95% CI [1.98, 2.21]; p < 0.001). Co-administration with opioids elevated the risk by 30%, while benzodiazepines increased it 2-fold. The CCTC analysis also detected an increased aOR of 1.36 (95% CI [1.12, 1.65]; p = 0.002) of receiving gabapentinoid treatment within 30 days prior to a drug poisoning event. The SCCS approach cannot completely exclude the effect of unmeasured time-varying confounders, such as transient changes in socioeconomic status, major life events, or illicit drug use, although the negative control analysis did not suggest meaningful residual confounding. Conclusions: The results suggest that gabapentinoid is associated with an increased risk of drug poisoning. Close monitoring throughout gabapentinoid treatment journey for drug poisoning is needed, especially at the initial phase. Concomitant use with opioid or benzodiazepines should be avoided.

Background: Evidence regarding the efficacy of adjunct statins to treat severe mental illness (SMI) is mixed. The varying pharmacokinetic properties of statins mean that specific statin-antipsychotic combinations might improve psychiatric symptoms. Objective: To test whether some statin-antipsychotic/mood stabiliser combinations result in psychiatric symptom improvement in patients with SMI, while others do not, using target trial emulation in observational data. Methods: We identified patients with SMI (schizophrenia, bipolar disorder, ‘other’ psychoses) prescribed antipsychotics/mood stabilisers and statins from 2000 to 2019 in English linked primary care records (Clinical Practice Research Datalink). We defined hypothetical randomised trials and observational emulations: (1) blood-brain barrier (BBB)-penetrant (simvastatin) versus non-penetrant (atorvastatin/pravastatin/rosuvastatin) statins; (2A) P-glycoprotein inhibitors (simvastatin/atorvastatin) versus non-inhibitors (pravastatin) in patients prescribed aripiprazole/risperidone/olanzapine (P-glycoprotein affinity); (2B) high (aripiprazole/risperidone/olanzapine) versus low (quetiapine) P-glycoprotein affinity antipsychotics in patients prescribed P-glycoprotein-inhibiting statins. Findings: We found no reduction in our primary outcomes (12-month psychiatric admissions) in trial 1 (HR 1.07, 95% CI 0.88 to 1.31); trial 2A (HR 0.77, 95% CI 0.28 to 2.15); or trial 2B (HR 0.93, 95% CI 0.79 to 1.09). In trial 2B, we observed lower self-harm events (HR 0.60, 95% CI 0.38 to 0.97) in per-protocol analysis and lower psychiatric admissions in the ‘other’ psychoses subgroup (HR 0.53, 95% CI 0.34 to 0.85). Conclusions: BBB penetrance appears unlikely to be the mechanism by which statins improve SMI symptoms. Interaction with P-glycoprotein may have some effect. Further mechanistic and clinical research is needed to understand statin-antipsychotic interactions and the role of interaction with P-glycoprotein. Clinical implications: There is currently not enough evidence to guide the prescription of statins for psychiatric symptom improvement in patients with SMI. If there is an effect of statins, it may be through specific statin-antipsychotic combinations.

Background: A higher prevalence of neurological conditions has been found in schizophrenia, bipolar disorder and other psychotic illnesses compared to the general population. We aimed to understand the cumulative prevalence of 15 neurological conditions in people with severe mental illness (SMI) from 5 years before to 5 years after their SMI diagnosis. Methods: We identified patients with SMI, aged 18–100 years from 1 Jan 2000 to 31 Dec 2018, from the UK Clinical Practice Research Datalink. Each SMI patient was matched 1:4 to individuals without SMI. The cumulative prevalence of 15 neurological conditions was recorded at 5, 3 and 1 years prior to SMI diagnosis; at SMI diagnosis; and 1, 3 and 5 years after SMI diagnosis. Prevalences were compared with logistic regression. Results: We identified 68 789 patients with SMI and 274 827 comparators. Of 15 neurological conditions, 13 (multiple sclerosis, cerebrovascular disease, dementia, ataxic disorders, epilepsy, Parkinson’s disease, other parkinsonism, paralysis, other movement disorders, cerebrospinal fluid disorders, cerebral palsy, disorders of nerve root, plexus or peripheral nerves and autonomic disorders) were more prevalent in SMI compared with comparators at the time of SMI diagnosis. Dementia (OR: 4.22; 95% CI 3.88 to 4.58), epilepsy (OR: 3.01; 95% CI 2.83 to 3.19) and Parkinson’s disease (OR: 3.97; 95% CI 3.45 to 4.57) were particularly elevated at 5 years post-SMI diagnosis. Conclusions: Many neurological conditions have higher prevalence in the SMI cohort compared with those without SMI. The different prevalence patterns observed in our study highlight the need to establish the causal pathways between specific SMI and neurological disease diagnoses.

Initially prescribed for schizophrenia and psychosis, antipsychotics are increasingly prescribed for other indications. Since the late 1990s, prescribing shifted from first-generation to second-generation antipsychotics. To examine overall initiation and prevalence of antipsychotic drug prescribing in UK primary care from 1995 to 2018, stratified by gender. Cohort studies using UK anonymised electronic primary care data from IQVIA Medical Research Data, including over 790 general practices and registered individuals aged 18-99 years. Antipsychotic drug initiation was stable in the late 1990s, at 6-7/1000 person-years at risk (PYAR) in men and 9-11/1000 PYAR in women. From 2001, initiation declined, stabilising from 2005 onward at 4/1000 PYAR in men and 4-5/1000 PYAR in women. Prevalence remained consistent from 1995 to 2018: 12/1000 in men and 14/1000 in women by 2018. Initiation and prevalence were higher in women than men, but increased with age in both genders: (18-39 v. 80-99 years; incidence rate ratio (IRR) 4.85, 95% CI 4.75-4.95 in men; IRR 5.90, 95% CI 5.78-6.02 in women; prevalence rate ratio (PRR) 2.22, 95% CI 2.19-2.25 in men; PRR 4.28, 95% CI 4.24-4.33 in women). Initiation and prevalence were greater in individuals with greater socioeconomic deprivation (Townsend score of 5 v. 1; IRR 2.69, 95% CI 2.64-2.75 in men; IRR 2.19, 95% CI 2.15-2.24 in women; PRR 3.87, 95% CI 3.82-3.92 in men; PRR 2.80, 95% CI 2.77-2.83 in women). Antipsychotic drug initiation decreased after 2001, stabilising from 2005 onward. Prevalence remained relatively consistent throughout the study period. Women had higher initiation and prevalence than men. However, both genders showed increased prescribing with age and socioeconomic deprivation.